Hepatitis B virus (HBV) is a small, enveloped DNA virus of the Hepadnaviridae family that has highly specific tropism for liver cells. Chronic infection leads to liver disease, hepatocellular carcinoma (HCC), liver cirrhosis, and other complications. Globally, almost 50% of all HCC cases are linked to chronic HBV infection. Currently, an estimated 240 million worldwide are chronically infected, and there are approximately 0.5-1 million deaths per year due to HBV-related liver conditions.
HBV has a partially double-stranded circular DNA genome, relaxed circular DNA (rcDNA), that is completed by host enzymes in the nuclei of newly infected cells to covalently closed circular DNA (cccDNA). The cccDNA is the template for viral transcripts, including a full-length pre-genomic RNA (pgRNA) that is packaged and reverse transcribed to rcDNA by the viral polymerase. The rcDNA can either enter the nucleus to amplify the cccDNA pool, or it can exit the cell in a mature virion.
Currently, HBV treatment options include only nucleoside reverse transcriptase inhibitors (NRTIs) and the immunomodulatory agent interferon alpha (IFN-α). NRTIs are able to clear the virus to undetectable levels; however, after cessation of therapy, patients' viral loads often rebound. This rebound is likely due to failure of NRTIs to clear the HBV cccDNA present in hepatocytes, and viral components are produced from the residual cccDNA, which can persist for decades. NRTI regimens, therefore, must be long-term, most likely lifelong. IFN-α treatment, on the other hand, is able to clear cccDNA, but virological response is only observed in <10% of patients. IFN-α treatment also leads to adverse side effects that often outweigh the potential benefits of treatment. New treatments, therefore, are highly desired for HBV therapy.